LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2

• Published in: International immunopharmacology 2017-08, Vol.49, p.6-12
• Main Authors: Yu, Yangyang, Zhang, Yuanyuan, Zhang, Yarui, Lai, Yihong, Chen, Wenwen, Xiao, Zhangang, Zhang, Wei, Jin, Meiling, Yu, Bo
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation analysis; AKT protein; Antimicrobial agents; Antimicrobial Cationic Peptides; Calcium; Calcium Signaling; Cathelicidins - metabolism; Cell activation; Cell Degranulation; Cells, Cultured; Chemical synthesis; Degranulation; Extracellular Signal-Regulated MAP Kinases - metabolism; G protein; Human mast cell; Humans; Interleukin 8; Interleukin-8 - metabolism; Leukocytes; LL-37; Mast Cells - physiology; Mrgx2; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NF-AT protein; NFATC Transcription Factors - metabolism; Peptides; Phosphatidylinositol 3-Kinases - metabolism; Protein kinase C; Receptors; Receptors, Formyl Peptide - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Lipoxin - metabolism; Receptors, Neuropeptide - genetics; Receptors, Neuropeptide - metabolism; Receptors, Purinergic P2X7 - metabolism; RNA, Small Interfering - genetics; Signal transduction; Signaling; Studies; Type C Phospholipases - metabolism; Up-Regulation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2017.05.016

Human LL-37 is an important class of cationic antimicrobial peptide (CAP) that is known to stimulate mast cell activation. While many studies have been conducted on LL-37, to date little is known about the functional receptors for LL-37-induced human mast cell activation, in particular in terms of the release of de novo synthesized mediators. Thus, the aim of the present study is to identify the functional receptors for LL-37-induced human mast cell activation in terms of the degranulation and release of de novo synthesized mediators and investigate the downstream signalling pathways involved in mast cell activation. Overall, our study importantly demonstrates that LL-37-induced human mast cell degranulation and release of de novo synthesized mediators function primarily through the activation of MrgX2. We furthermore show that LL-37-induced human mast cell line LAD2 cells are involved in the degranulation and release of IL-8, and that FPRL1 and P2X7 have only a partial effect on IL-8 release, and no effect on mast cell degranulation triggered by LL-37. Instead, we find that silencing the expression of MrgX2 in human mast cell significantly inhibits the LL-37-induced degranulation and release of IL-8. Overall, this effect is associated with the activation of the Gi protein, PLC/PKC/Calcium/NFAT, PI3K/Akt and MAPKs signalling pathways. [Display omitted] •MrgX2 is required for preformed mediator release in LL-37-triggered mast cells.•MrgX2 is required for newly formed mediator release in LL-37-triggered mast cells.•FPRL1 and P2X7 have only a partial effect on mast cells IL-8 release by LL-37.